The goal of this proposal is to enhance our understanding of tyrosine kinase-mediated signaling pathways via evolutionary genomic approaches. Tyrosine kinases are key components of metazoan signal transduction and their mutant forms are some of the most well characterized oncogenes. They also belong to a large gene family mediating a diverse range of cellular processes. I propose to determine the evolutionary relationships among tyrosine kinases. This will be carried out by phylogenetic analysis of all available tyrosine kinase sequences. The phylogeny will provide a framework for determining differential expansion of subfamilies and functional divergence of the tyrosine kinase family in metazoans. Functional divergence among tyrosine kinases can be attributed to changes in amino acid sequences and/or gene expression. I propose to determine amino acid sites contributing to functional divergence between duplicates or subfamilies of? tyrosine kinases. These sites will be identified by examining amino acids showing site-specific rate difference or different selection regimes. These predictions will be valuable in functional genomic analysis and in understanding the mechanisms governing fates of duplicated genes. As a first step to understand the evolution of signaling pathways, I propose to reconstruct the evolutionary history of components in the signaling pathways. In particular, I will determine the presence/absence and the relationships between homologs of the selected components in the ErbB signal transduction pathways. The timing when these components arose will allow further analysis on the timing of signaling component incorporation.